Celiac disease, also called
celiac sprue is one of the most common enteropathic disorders and
is characterized by a lifelong hypersensitivity to gluten proteins
found in wheat, rye, oat and barley.
In early childhood the immunological intolerance to gluten, or more
precisely the soluble protein fraction gliadin, leads to a chronic
inflammatory response in the small-intestinal mucosa and subsequent
malabsorption characterized by chronic diarrhea, steatorrhea and failure
to thrive. Many adult patients can also show other atypical signs
such as , abdominal distention , weight loss, fatigue, skin- and joint
problems or migraine-like headache. Indeed, others may remain largely
asymptomatic.
Until recently, celiac disease was considered relatively uncommon
with an estimated prevalence rate ranging form 1 in 1000 to 1:4000.
However, the availability of new serologic tests have led to the observation
that celiac disease is much more common, affecting about 1 of 100-400
persons in Europe as well as in North America, the majority of patients
showing little clinical symptoms.
Considerable evidence now indicates that celiac disease has a strong
genetic component. The incidence among first degree relatives has
been estimated at 10-15% and among monozygotic twins at about 75%.
Moreover, its now clear that celiac disease is association with the
expression of the human leukocyte antigen (HLA) class 11 molecules
DQ2 or DQ8. However, at least one other non-HLA gene and some environmental
factors are also likely to be involved in the disease.
The MHC class ll are cell surface molecules involved in presenting
foreign antigen to T-helper cells. They are encoded by the genes HLA-DR,
DQ and -DP. Each MHC molecule is a heterodimer consisting of an α-
and a β-chain. In the case of the DQ molecule, the α-chain is
encoded by the HLA-DQA1 and the β-chain by the HLA-DQB1 gene.
The genes HLA-DQA1 and HLA-DQB1 are both polymorphic.,that is, a number
of different alleles exist in the population. Molecular genetic testing
has shown that the DQ2 heterodimer consists of the chains α1*0501
and ß*0202, coded by the alleles DQ A1*0501 and DQB1*0201, respectively.
About 95% of all celiac patients possess this particular genotype
compared to approximately 20% of the normal population. Of the few
coeliac patients who are negative for DQ(α1*0501, β1*0201),
a great majority are HLA-DRB1*04 positiv.
The DQ (α1*0501, β1*0201)
heterodimer may serve as a diagnostic marker for coeliac disease,
much like HLA-B*27 in ankylosing spondylitis. In individuals with
gastrointestinal malfunction and in whom a biopsy is perhaps not possible,
the presence of DQ2 would certainly support a diagnosis of CD. On
the other hand, the absence of DQ2 or DR4 most likely excludes CD.
HLA typing should be especially useful in identifying individuals
in celiac disease families with a high risk for the disease. Due to
gene dosage effects, homozygosity for the DQ β1*0201
allele may determine an earlier onset and a more severe clinical presentation
of the disease. Therefore the evaluation of the genotype is the only
practical approach to determine a clinical progression and to prevent
from more severe complications.
Early diagnosis is also important to ensure that the individual begins
a gluten-free diet as soon as possible. Untreated celiac disease is
associated with other autoimmune disorders, including type 1 diabetes
(IDDM) and rheumatoid arthritis. It has been suggested that chronic
lymphocyte stimulation in the intestine in celiac patients could result
in an increase in autoantibody production and therefore stimulate
the development of other autoimmune disorders. The prevalence of celiac
disease in patients with IDDM for example is approximately 3 to 8
percent. It has also been shown that in patients with rheumatoid arthritis,
some of their symptoms can disappear when on gluten-free diets.
Genotyping for DQ2 and DR4 may be more useful than serological testing
of gliadin-, endomysial- and tissue transglutaminase-antibodies. Most
of all, false negative results due to IgA deficiency, in children
under two years of age, or in patients with mild enteropathy, could
be avoided by molecular testing. In addition all serological parameters
become normal in patients who are on a strict gluten-free diet, whereas
genotyping is the only possibility to verify and confirm an initial
diagnosis.
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